CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICA TION NUMBER:
`
`NDA 20-717/S—004
`
`Name:
`
`Provigil Tablets
`
`Generic Name:
`
`modafinil
`
`Sponsor:
`
`Cephalon, Inc.
`
`Approval Date: .
`
`11/05/01
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICA TI0N NUMBER:
`
`NDA 20—717/s—oo4
`
`CONTENTS
`
`Reviews / Information Included in this Review
`
`A roval Letter
`
`A: ”a rovable Letter s
`Final Printed Labelin_
`
`Medical Review s
`
`Chemist Review s
`
`'
`
`'
`
`Administrative and Corres ondence Document s
`
`EA/FONSI
`
`Pharmacolo Review s
`Statistical Review(s)
`
`Microbiolo_ Review(s
`' Clinical Pharmac0105 /Bio n harmaceutics Review s
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICA TIONNUMBER:
`
`NDA 20-717/S—004
`
`APPROVAL LETTER
`
`

`

`/: DEPARTMENTOFHEALTH& HUMANSERVICES
`“in?
`
`Public Health Service
`Food and Drug Administration
`Rockville MD 20857
`
`NDA 20—717/S-004
`
`Cephalon, Inc.
`Attention: Kenneth L. White, PharmD.
`
`Vice President, Regulatory Affairs
`145 Brandywine Parkway
`West Chester
`PA 19380-4245
`
`Dear Mr. White:
`
`Please refer to your supplemental new drug application dated July 13, 2001, received July 16, 2001 ,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Provigil (modafinil)
`Tablets, 100 mg and 200 mg.
`
`This supplemental new drug application provides for the addition of an alternate manufacturing site,
`Catalytica, NC, for the manufacture of Provigil Tablets.
`
`We acknowledge receipt of your submission dated October 25, 2001.
`
`We have completed the review of this supplemental application as amended, and it is approved.
`
`We remind you that you must comply with the requirements for an approved NDA set forth under
`21 CFR 314.80 and 314.81.
`
`If you have any questions, call Anna Marie Homonnay, R.Ph., Regulatory Project Manager, at (301)
`594-5535.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Maryla Guzewska, Ph.D.
`Chemistry Team Leader, Neurology Drugs for the
`Division of Neuropharmacological Drug Products,
`(HFD— 1 20)
`DNDC I, Office of New Drug Chemistry
`Center for Drug Evaluation and Research
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Maryla Guzewska
`11/5/01 02:56:00 PM
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH J
`
`APPLICA TION NUMBER:
`
`NDA 20—717/S-004
`
`CHEMISTRY REVIEWg S!
`
`

`

`CHEMIST'S REVIEW
`OF SUPPLEMENT
`
`ORGANIZATION:
`NDA NUMBER:
`SUPPLEMENT NUMBER:
`
`LETTER DATE
`STAMP DATE
`AMENDMENTS:
`LETTER DATES
`STAMP DATES
`
`APPLICANT NAME AND ADDRESS:
`
`NAME OF DRUG:
`NONPROPRIETARY NAME:
`
`RECEIVED BY CHEMIST:
`Cephalon, lnc.
`145 Brandywine Parkway
`West Chester, PA 19380-4245
`Provigil®
`Modafinil
`
`CHEMICAL NAMEI STRUCTURE: 2-[(Diphenylmethyl)sulfinyl]acetamide ,
`
`HFD-120
`20-717
`SCM-004
`
`13-JUL-01
`16-JUL—01
`
`25-OCT-01
`26-OCT-09
`
`18-JUL-O1
`
`DOSAGE FORM(s):
`POTENCY(IES):
`PHARMACOLOGICAL CATEGORY:
`SPECIAL PRODUCTS:
`How DISPENSED:
`RECORDS / REPORTS CURRENT:
`RELATED IND / NDAI DMF(S):
`
`Tablets
`100 mg, 200 mg
`Narcolepsy
`(YES)
`XX (Rx)
`XX (YES)
`
`,
`XX (NO)
`(OTC)
`(NO)
`
`SUPPLEMENT PROVIDES FOR: The addition of an alternate manufacturing site, Catalytica, NC, for the drug
`product.
`
`COMMENTS: This is a PA supplement for a SUPAC L3 change. The sponsor describes minor changes in the
`manufacturing and packaging as a result of the Site transfer. The supplement contains batch records of the
`validation batches from the new site as well as their release batch results. The amendment dated October 25
`provides comparative multi-point dissolution data to support the site transfer. These data were reviewed by the
`Biopharmaceuticals Division. The dissolution profiles at the two manufacturing Sites were concluded to be
`similar (see Biopharm. Review dated October 31, 2001). Available stability results are also provided. All six
`batches meet the same specifications as approved in the NDA. The testing methods remain the same and
`have undergone technology transfer. Labeling is adjusted to reflect the additional site and new identification
`numbers. The site was inspected and received an Acceptable recommendation from the Office of Compliance
`(see EER in CMC Review Notes).
`
`CONCLUSIONS AND RECOMMENDATIONS: Recommend Approval based on 00 and Biopharmaceutical Division
`recommendations.
`
`REVIEWER NAME
`
`SIGNATURE
`
`Mona Zarifa, Ph.D.
`cc: Orig: NDA 20-717
`HFD-120/Div. File
`HFD-120/Ahomonnay/Mzarifa/MGuzewska
`
`'
`
`lNlT: MGuzewska
`
`DATE COMPLETED
`
`November 5, 2001
`
`Filename: 2071754.doc
`
`

`

`Redacted 4 page(s)
`
`1 of trade Secret. and/Or ,
`
`confidentialcommercial ,
`
`»
`
`‘
`
`1
`
`information from
`
`
`
`

`

`-————-——.-—-——-———_——.--m—u—_--__—-_——_—_________—____——-—-———_______.—_—-_—-—————_
`
`ThisIs a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Mona Zarifa
`
`11/5/01 02:45:36 PM
`CHEMIST
`
`Maryla Guzewska
`11/5/01 02:50:01 PM
`CHEMIST
`
`

`

`CENTER FOR DRUGEVALUATION AND RESEARCH
`
`APPLICA TION NUMBER:
`
`NDA 20-717/S-004
`
`CLINICAL PHARMACOLOGY/
`
`BIOPHARMACEUTIC S REVIEW! S 2
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW
`
`Submission Date:
`
`7/13/01, 10/25/01
`
`20-717/SCM-004
`NDA:
`Provigil® (modafinil) 100mg and 200mg Tablets
`Drug Name:
`Narcolepsy
`Indication:
`Cephalon Inc. West Chester PA
`Sponsor:
`Type of Document: CMC Site Change Supplement
`Reviewer:
`Hong Zhao, Ph.D.
`
`Introduction
`
`-
`
`The purpose of this Supplement is to provide data to support the addition of DSM
`Catalytica Pharmaceuticals, Inc., Greenville, NC (Catalytica) as an alternate site to
`manufacture, package and perform analytical testing of PROVIGIL drug product (100
`and 200 mg) Tablets for commercial use.
`
`Dissolution Data Review
`
`Multipoint dissolution profile data were generated using the NDA approved dissolution
`method (USP Dissolution Apparatus II, a paddle speed of 50 rpm and 900 mL 0.1 N HCl
`dissolution medium):
`
`Mean % Dissolved iSD
`
`Time (min)
`15
`30 ‘
`45
`6O
`
`E:
`153 8-FL5
`80:10.2
`94:6.3
`97:49
`99i4.2
`
`j(N=12)
`153 8-FL15
`82i9.8
`93i7.8
`99i5.6
`100i5.2
`
`(100 mg Tablet)
`
`Catalytica (N*=l8)
`9K6019
`9L6002
`79i5.4
`77i8.0
`95-1-23
`93i5.2
`981-20
`95i4.4
`98il.8
`96i4.l
`
`1538-FL2
`8816.5
`97321.2
`98i0.6
`98i0.6
`
`15
`30
`45
`60
`
`j (N=6)
`E
`153 8-FL4
`79i3.6
`93i1.6
`96il.1
`96il .2
`
`(200 mg Tablet)
`1538-FL6
`79i4.5
`95i1.5
`98i0.9
`98i0.8
`
`1538-FL8
`76fl.9
`91i1.2
`95i0.9
`96i0.8
`
`050960
`77:6.7
`92i3.4
`97i2.7
`#
`
`Catalytica (N*=18)
`9K6020
`73i8.2
`91:27
`95i1.6
`96il .3
`
`N*=l 8 values derived from 6 beginning + 6 middle + 6 end samples. # Sampling stopped at 45 minutes.
`
`Lot Summary
`Lot #
`1538-FL5
`
`1538-FL15
`
`9L6002
`9K6019
`1538-FL2
`1538—FL4
`1538-FL6
`1538-FL8
`050960
`9K6020
`
`Strength
`100 mg
`
`100 mg
`
`100 mg
`100 mg
`200 mg
`200 mg
`200 mg
`200 mg
`200 mg
`200 mg
`
`Manufacturer
`
`E
`
`]
`
`Catalytica
`Catalytica
`
`Catalytica
`
`]
`
`Description
`NDA Regis. @
`
`NDA Regis. @[
`
`Pilot lot
`Pilot lot
`NDA Regis. @J
`NDA Regis. @
`NDA Regis. @
`NDA Regis. @
`Recent Commercial lot
`Pilot lot
`
`

`

`Summary
`0 The regulatory dissolution specification for PROVIGIL Tablets is NLTE]% in 45
`minutes.
`
`0 The dissolution performance for all lots tested meet the regulatory specification for
`PROVIGIL Tablets.
`
`1 site and the proposed site (Catalytica)
`0 PROVIGIL Tablets manufactured at I:
`dissolved rapidly with >90% of the drug dissolved in 30 minutes for all the lots
`tested.
`
`Comment 1
`
`PROVIGIL Tablets 100 and 200 mg manufactured at the proposed site (Catalytica) have
`similar dissolution profiles as compared to that of the drug products manufactured at the
`approved site I:
`1 .
`
`Recommendation
`
`Please convey Comment 1 to Chemistry Review team.
`
`Hong Zhao, Ph.D.
`
`RD/FT Initialed by Raman Baweja, Ph.D.
`
`cc: NDA 20-717 (CMC Site Change Supplement), HFD-120, HFD—860 (Zhao, Baweja,
`Mehta), Central Documents Room (CDR-Biopharm)
`
`

`

`
`
`
`
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`____.__——__________--—_______._—_____..__-——-—--_—___——-___-______————___-____———--
`
`Hong Zhao
`10/31/01 03:25:57 PM
`BIOPHARMACEUTICS
`
`Raman Bawej a
`10/31/01 04:14:45 PM
`BIOPHARMACEUTICS
`
`

`

`CENTER FOR‘DRUG EVALUATION AND RESEARCH
`
`APPLICATIONNUMBER;
`NDA 20-717/S-004
`
`‘ ADMINISTRATIVEand '
`CORRESPONDENCE DOCUMENTS
`
`

`

`4 DEPARTMENT OF HEALTH & HUMANSERVICES
`
`Public Health Service
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 20-717
`
`PRIOR APPROVAL SUPPLEMENT
`
`Cephalon, Inc.
`Attention: Paul M. Kirsch
`
`Director, U.S. Regulatory Operations
`145 Brandywine Parkway
`West Chester, PA 19380-4245
`
`Dear Mr. Kirsch,
`
`We have received your supplemental drug application submitted under section 505(b) of the Federal
`Food, Drug, and Cosmetic Act for the following:
`
`Name of Drug Product:
`
`PROVIGIL (modafmil) Tablets
`
`NDA Number:
`
`20-717
`
`Supplement number:
`
`S-004
`
`Date of supplement:
`
`July 13, 2001
`
`Date of receipt:
`
`July 16, 2001
`
`Unless we notify you within 60 days of the receipt date that the application is not sufficiently complete to
`permit a substantive review, this application will be filed under section 505(b) of the Act on September
`16, 2001 in accordance with 21 CFR 314.101(a).
`
`All communications concerning this supplement should be addressed as follows:
`
`US. Postal Service:
`
`Center for Drug Evaluation and Research
`Division of Neuropharmacological Drug Products, HFD-120
`Attention: Division Document Room, 4008
`5600 Fishers Lane
`
`Rockville, Maryland 20857
`
`

`

`NDA 20-717
`
`Page 2
`
`Courier/Overni ght Mail:
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Neuropharmacological Drug products, HFD-120
`Attention: Division Document Room, 4008
`1451 Rockville Pike
`
`Rockville, Maryland 20852
`
`If you have any questions, call Anna Marie Homonnay, R.Ph., Regulatory Management Officer, at (301)
`594-2850.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Maryla Guzewska, Ph.D.
`Chemistry Team Leader, Neurology Drugs for the
`Division of Neuropharmacological Drug Products
`(HFD-120)
`DNDC 1, Office of New Drug Chemistry
`Center for Drug Evaluation and Research
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Maryla Guzewska
`8/1/01 01:27:27 PM
`
`